Infancy‐onset diabetes caused by de‐regulated AMPylation of the human endoplasmic reticulum chaperone BiP

Author:

Perera Luke A1ORCID,Hattersley Andrew T2ORCID,Harding Heather P1ORCID,Wakeling Matthew N2,Flanagan Sarah E2,Mohsina Ibrahim3,Raza Jamal3,Gardham Alice4,Ron David1ORCID,De Franco Elisa2ORCID

Affiliation:

1. Cambridge Institute for Medical Research University of Cambridge Cambridge UK

2. Institute of Biomedical and Clinical Science, College of Medicine and Health University of Exeter Exeter UK

3. Department of Endocrine and Diabetes National Institute of Child Health Karachi Pakistan

4. North West Thames Regional Genetics Service Harrow UK

Abstract

AbstractDysfunction of the endoplasmic reticulum (ER) in insulin‐producing beta cells results in cell loss and diabetes mellitus. Here we report on five individuals from three different consanguineous families with infancy‐onset diabetes mellitus and severe neurodevelopmental delay caused by a homozygous p.(Arg371Ser) mutation in FICD. The FICD gene encodes a bifunctional Fic domain‐containing enzyme that regulates the ER Hsp70 chaperone, BiP, via catalysis of two antagonistic reactions: inhibitory AMPylation and stimulatory deAMPylation of BiP. Arg371 is a conserved residue in the Fic domain active site. The FICDR371S mutation partially compromises BiP AMPylation in vitro but eliminates all detectable deAMPylation activity. Overexpression of FICDR371S or knock‐in of the mutation at the FICD locus of stressed CHO cells results in inappropriately elevated levels of AMPylated BiP and compromised secretion. These findings, guided by human genetics, highlight the destructive consequences of de‐regulated BiP AMPylation and raise the prospect of tuning FICD's antagonistic activities towards therapeutic ends.

Funder

Diabetes UK

Bureau for Economic Growth, Education, and Environment, United States Agency for International Development

Wellcome Trust

Publisher

Springer Science and Business Media LLC

Subject

Molecular Medicine

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